Open projects at Department of Chemistry

• kemi.dtu.dk/mhc/
• The Clausen research group has a special interest in chemical biology, i.e. using synthetic chemistry to provide tool compounds for answering biological questions. This overall research theme currently includes HTS and FBDD against protein and RNA targets, medicinal chemistry related to oncology, inflammatory and infectious diseases, prodrug design and synthesis, vaccine development, plant polysaccharides, and new materials from plant cell wall components.

• https://www.bric.ku.dk/research-groups/Research/lund_group/
• The Lund group is interested in ribosomes, molecular machines that decode genetic information to produce proteins. Evidence from all branches of life demonstrate that ribosomes are heterogeneous, varying with respect to protein composition or RNA modification. Remarkedly, it is unknown how this heterogeneity contributes to the well-described instalment of translation programs. These programs are essential for cellular differentiation and organismal development. In addition, translation programs are likely hijacked in diseases. A main aim of the group is to identify ribosome subtypes, determine their composition, and understand how different ribosome subtypes conducts selective mRNA translation.

• What?
  • Deregulated protein translation is a hallmark of many diseases including cancers. The ribosome is the central hub for protein translation across all life forms and recent evidence demonstrate that the ribosome is not a homogenous machine but comes in several subtypes with variations in associated proteins and modifications of the ribosomal RNA. Importantly, data from several cancer types show that the ribosomes in cancer are differentially modified compared to healthy tissues. This strongly suggests that specific ribosome subtypes are selected for in cancer to facilitate the increased need for protein production as well as instigation of translation programs supporting cancer development. Importantly, there is evidence that these “oncoribosomes” are structurally distinct and therefore could constitute a new opportunity for therapeutic intervention. Together, we will look to identify small molecules that bind to oncoribosomes and potentially develop them into useful tool compounds for studying oncoribosomes and starting points for drug discovery.
• How?
  • We will identify small molecule ligands using fragment-based screening by ¹⁹F NMR. The targets investigated will be both full size ribosomes as well as model RNA containing disease-relevant modifications. Ribosomes are routinely produced in the Lund lab, and during the project, we will establish techniques for producing modified RNA in the Clausen lab (automated chemical synthesis, in vitro transcription, and ligation). Main responsibilities of the PhD candidate will be RNA synthesis, screening by NMR, fragment-to-lead chemistry, and validation of the small molecule ligands in relevant assays.
• Why?
  • If we can discriminate between modified, disease-specific ribosomes (oncoribosomes) and ribosomes from non-malignant tissue with small molecules, it opens up many opportunities for improved diagnostics and therapy in oncology. Furthermore, such small molecules can be excellent research tools for studying (differential) ribosome function.

If you undertake this collaborative project, you will be trained by teams with expertise in medicinal chemistry (synthesis, assay development, screening) and cancer biology (cell biology, RNA structure and function, sequencing). The project can only be realized through a close interplay between the research environments and the team members, contributing their expertise in different areas of the project. You will be based at the Department of Chemistry, Technical University of Denmark, but will also experience working at the Biotech Research and Innovation Centre, University of Copenhagen. The interdisciplinary aspects of this PhD project rest on the collaboration between the Clausen group (DTU) and the Lund group (BRIC). The project involves aspects of human cell biology (molecular biology, RNA biology) and medicinal chemistry (screening, chemical biology, and synthesis). The interdisciplinarity will manifest itself most clearly through the interplay of compound evaluation, target selection, and evaluation of consequences of RNA functional modulation. Structural biology, medicinal chemistry, and cancer biology will come together to drive the development of functional small molecules, informed by cell and structural biology as well as bioinformatic analysis. It’s essential to discriminate between rRNA with disease-specific modifications (oncoribosomes) and rRNA from healthy cells. The project builds on an ongoing collaboration between the Lund group (RNA biology, oncology), the Montoya group (structural biology, cryo-EM), and the Clausen lab (NMR screening, medicinal chemistry). The ongoing project will provide a solid starting point for the fellow to pursue successful strategies for functional modulation of RNA function related to disease.

• kemi.dtu.dk/mhc/
• The Clausen research group has a special interest in chemical biology, i.e. using synthetic chemistry to provide tool compounds for answering biological questions. This overall research theme currently includes HTS and FBDD against protein and RNA targets, medicinal chemistry related to oncology, inflammatory and infectious diseases, prodrug design and synthesis, vaccine development, plant polysaccharides, and new materials from plant cell wall components.

• https://www.bric.ku.dk/research-groups/Research/wennerberg-group/
• The Wennerberg group is interested in discovering precision cancer therapeutic approaches that target cancers for which there are few or no good treatments today, including the specific cancer cell subsets that survive current therapies and eventually cause the cancer to grow back. To accomplish this, they utilize primary cancer cell culture models, with or without immune cells, and study how different subpopulations in the cell culture models respond to treatments at the phenotypic and molecular levels.

• What?
  • Immunotherapy is currently revolutionizing cancer therapy by harnessing the power of the innate and adaptive immune system against cancer cells, thus providing a more tumor-selective approach in assistance to traditional treatments. The identification of tumor-associated carbohydrate antigens (TACAs), aberrant types of glycans decorating the surface of tumor cells, has paved the way for the development of a new type of cancer active immunotherapy focusing on carbohydrate-based cancer vaccines. We have developed vaccine candidates based on ganglioside-type TACAs (expressed in melanoma, small cell lung cancer, and neuroblastoma) and the glycolipid agonist α-galactosylceramide (αGalCer). The synthetic TACA-(αGalCer) conjugates are used in a versatile liposomal delivery platform, can stimulate iNKT cells, and raise IgG antibodies against glycan tumor epitopes, independently from individual polymorphisms. In this project, we will further investigate the activation of immune cells, with a special focus on variations to the adjuvant and how that affects primary human cells in co-culture studies.
• How?
  • We will synthesize variations of α-galactosyl ceramide that is known to work well on human receptors. These will be studied and compared in combination with TACA antigens using our established liposomal delivery system. We will look at stimulation of different types of immune cells in advanced cancer cell culture models.
• Why?
  • The aim is to generate knowledge that can support the development of a therapeutic cancer vaccine for small-cell lung cancer. We also expect that the data can more broadly support our platform for vaccines based on the activation of iNKT cells. Additionally, the cancer models investigated could prove to be useful for other aspects of cancer research and precision medicine.

If you undertake this collaborative project, you will be trained by teams with expertise in medicinal chemistry and vaccine development (synthesis, formulation, animal studies, cell biology) and cancer biology (cell biology, precision medicine, advanced cancer cell models). The project can only be realized through a close interplay between the research environments and the team members, contributing their expertise in different areas of the project. You will be based at the Department of Chemistry, Technical University of Denmark, but will also experience working at the Biotech Research and Innovation Centre, University of Copenhagen. The interdisciplinary aspects of this PhD project rest on the collaboration between the Clausen group (DTU) and the Wennerberg group (BRIC). The project involves aspects of human cell biology (cancer cell cultures, molecular biology) and medicinal chemistry (synthesis, formulation, screening). Specifically, we will test combinations of adjuvants (synthesized at DTU) in our preferred liposome formulation and study the effect in cancer cell models (established at BRIC). The outcome (immune cell activation, cytokine levels, effects on cell growth) will inform a vaccine formulation that will be investigated in murine cancer models.

• https://www.dtu.dk/english/person/katrine-qvortrup?id=54449&entity=profile 
• We use small organic chemistry to approach a wide variety of challenges in chemical biology. Current focus is directed against cancer, brain diseases, and protein modification. Research efforts are aimed at the development of screening technology, new chemical probes, diagnostic tools, and lead compounds for drug discovery.

• https://www.rigshospitalet.dk/english/departments/centre-for-cancer-and-organ-diseases/research/finsen-laboratory/research/Pages/engelholm-group.aspx
• The Engelholm group at BRIC focuses on cancer invasion and stromal targeting using molecular and cellular biology approaches. A key theme is the development of novel therapeutic strategies, including antibody-drug conjugates (ADCs), targeting hard-to-treat cancers like glioblastoma. Using advanced cancer models, we study tumor heterogeneity and drug delivery barriers to develop transformative therapies. This interdisciplinary work bridges translational oncology and chemical biology for innovative solutions.

• What?
  • Novel targeted therapies against hard-to-treat brain cancers
• How?
  • Guided by understanding of glioblastoma and cancer invasion at the molecular level, we will use chemical design and protein modification approaches to decorate antibodies for development of antibody–drug conjugates (ADCs) in treatment of Glioblastoma multiforme (GBM). The development of ADCs for treatment of GBM is complicated due to (1) the inherent heterogeneity of GBM, (2) the difficulties of transporting large biomolecules across the brain barriers. Recognizing the inherent heterogeneity of GBM, we will follow a dual-faceted approach by (1) Trying different receptor targets to find the best candidate for combating of GBM, (2) Explore the use of shuttle receptors expressed  by the blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB), respecitively, hereby investigating direction of the ADCs efficiently to both the brain cortex and ventricles. Through this dual-faceted approach, we aim to enhance the delivery and efficacy of our therapeutic agents, marking a pivotal step towards GBM treatment modalities.
• Why?
  • Glioblastoma multiforme (GBM) is an aggressive and fatal malignancy that has limited therapeutic Treatment is seriously limited by the low penetration of the brain barriers (BBs), making drug delivery almost impossible. ADCs have demonstrated superior efficacy and reduced toxicity in a range of cancers but their application in treatment of brain tumors has limited success due to limited transport across the BBs.

Our initiative joins synergistic and complementary competences to develop improved strategies for treatment of ‘hard-to-treat’ brain cancers. Lars Engelholm will use his understanding of glioblastoma and cancer invasion at the molecular level and ADC development to guide the chemical design of brain targeting ADCs, while Katrine will use her knowledge on protein modification and brain barrier shuttle mechanisms to guide the development of brain-targeting ADCs.

The project will be divided into following objectives:

1. Refinement of antibodies and ADCs: This objective includes modifying antibodies and ADCs to enhance their effectiveness for subsequent in vivo Antibody modification will be performed at DTU, while in vivo testing will be performed at BRIC. This objective involves refining and testing antibodies. Initially, we will study antibodies without conjugated cytotoxic payloads to assess their binding, specificity, and ability to cross brain barriers. These studies will inform subsequent ADC development. Later efforts will use antibodies functionalized with various payloads, exhibiting different mechanisms of action (MoA), including DNA-damaging agents (PNU), tubulin inhibitors (MMAE), and topoisomerase inhibitors (DXD). In addition, selected antibodies will be modified with PET tracers to enable real-time imaging and evaluation of brain uptake in vivo.
2. Exploration of strategies to enable brain delivery (performed at DTU): This includes testing both conventional and bi-specific ADC’s to facilitate the transport of therapeutic agents across the blood-brain barrier. These approaches will integrate antibody design with targeting mechanisms to enhance therapeutic delivery while maintaining efficacy against glioblastoma. Antibodies will be functionalised with ligands targeting shuttle receptors expressed by either the blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB).
3. Evaluation of ADC efficacy (performed at BRIC): Using our ‘in-house’ syngeneic orthotopic GBM mouse models that accurately represent the complexities of GBM, this objective includes evaluation of brain distribution as well as investigating the therapeutic effect on GBM.

The PhD-student in the project will perform work at both DTU (supervised by Qvortrup) and BRIC/Finsen Laboratory (supervised by Engholm), which are located close to each other.